Gutenberg Open Science: 2-sulfonylpyrimidines as privileged warheads for the development of S. aureus sortase A inhibitors

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8873

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DC Field	Value	Language
dc.contributor.author	Barthels, Fabian	-
dc.contributor.author	Meyr, Jessica	-
dc.contributor.author	Hammerschmidt, Stefan J.	-
dc.contributor.author	Marciniak, Tessa	-
dc.contributor.author	Räder, Hans-Joachim	-
dc.contributor.author	Ziebuhr, Wilma	-
dc.contributor.author	Engels, Bernd	-
dc.contributor.author	Schirmeister, Tanja	-
dc.date.accessioned	2023-03-02T11:02:25Z	-
dc.date.available	2023-03-02T11:02:25Z	-
dc.date.issued	2021	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/8889	-
dc.description.abstract	Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar KI values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the SNAr reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog.	en_GB
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	570 Biowissenschaften	de_DE
dc.subject.ddc	570 Life sciences	en_GB
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	2-sulfonylpyrimidines as privileged warheads for the development of S. aureus sortase A inhibitors	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-8873	-
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 09 Chemie, Pharmazie u. Geowissensch.	de
jgu.organisation.number	7950	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Frontiers in molecular biosciences	de
jgu.journal.volume	8	de
jgu.pages.alternative	804970	de
jgu.publisher.year	2021	-
jgu.publisher.name	Frontiers	de
jgu.publisher.place	Lausanne	de
jgu.publisher.issn	2296-889X	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	570	de
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.3389/fmolb.2021.804970	de
jgu.organisation.ror	https://ror.org/023b0x485	-
Appears in collections:	JGU-Publikationen

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